Stem cell-based culture system for drug development

Abstract

The present invention relates to culture systems comprising differentiated stem cells, that may be used for identifying agents useful in treating degenerative nervous system disorders and are suitable for high-throughput screening applications. It is based, at least in part, on the discovery that co-cultures of (i) astrocytes expressing a mutated SODI gene and (ii) stem-cell derived motor neurons manifested cell death via a Bax-dependent mechanism, and modeled motor neuron death in amyotrophic lateral sclerosis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a §371 national stage application of PCT International Application No. PCT / US2008 / 059883, filed Apr. 10, 2008, and claims the benefit of U.S. Provisional Applications Nos. 60 / 915,837, filed May 3, 2007 and 60 / 911,824, filed Apr. 13, 2007, the contents of all of which are hereby incorporated by reference into this application.GRANT SUPPORT[0002]This invention was made with government support under Grant Nos. NS42269, NS38370, NS11766, AG 21617, ES013177 and DK58056 awarded by the United States National Institutes of Health and Grant No. DAMD 17-03-1 awarded by the United States Department of Defense. The government has certain rights in the invention.1. INTRODUCTION[0003]The present invention relates to culture systems, comprising differentiated stem cells, that may be used for identifying agents useful in treating degenerative nervous system disorders and are suitable for high-throughput screening applications.2. BACKG...

AI Technical Summary

Benefits of technology

The present invention is about a new way to create and use stem cells to develop new treatments for degenerative nervous system disorders, like ALS. The invention is based on the discovery that when certain types of cells are mixed together, they can die in a way that mimics motor neurons dying in ALS. Using stem cells that have already been directed to become motor neurons, the invention creates a system where multiple cultures can be tested simultaneously, making the process more efficient and reliable. Overall, this invention provides a way to identify new treatments for neurodegenerative diseases like ALS.

Problems solved by technology

Although motor deficit usually predominates in the limbs, bulbar enervation can be severely involved, sometimes early in the course of the disease, leading to atrophy of the tongue, dysphagia, and dysarthria.

To date, only a few approved treatments, such as mechanical ventilation and riluzole, do prolong survival in ALS patients to some extent.

However, the development of more effective neuroprotective therapies is impeded by our limited knowledge of the actual mechanisms by which motor neurons die in ALS, and of how the disease propagates and progresses.

However, despite intense research efforts, the nature of the adverse property manifested by mutant SOD1 remains elusive.

This gene, however, is only partially functional, and thus SMN2 is unable to fully compensate for the SMN1 defect [54].

While significant strides have been made over the past decade in unraveling the neurobiology of SMA, the function of the SMN protein still remains incompletely elucidated [54].

However, since a low level of SMN is noxious to all cells, one cannot exclude that reduced SMN levels contribute to the disease phenotype by also affecting non-neuronal cells such as glia.

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